The goal of this project is to validate the "protease hypothesis" of human emphysema development, which proposes that phagocytic cells in the lung release elastase into the alveolar interstitium where it binds to and degrades elastin. We will utilize recently developed ultrastructural, immunological staining techniques, and morphometry to determine the distribution and relative quantity of elastase associated with elastic fibers in specimens from lungs of patients undergoing resection for bronchogenic carcinoma. We have evidence that peptides released from the elastic fibers during the destructive process appear in the blood. Therefore, we propose to measure the plasma levels of elastin-derived peptides of these patients. With the initiation of elastin destruction, it is proposed that there is accumulation of interstitial cells which are stimulated to synthesize and secrete elastin. Immunological staining methods which can localize both the extracellular elastin in the lung as well as the intracellular elastin within the organelles of the interstitial cells will be utilized. The technique will be valuable to study the repair-response induced during elastin destruction, by quantifying the relative number of interstitial cells stimulated to produce elastin. We propose to determine if there is a relationship between elastase release, elastin destruction and resynthesis, and the histopathology, pulmonary function and smoking history of various patient populations when lung specimens are examined after pneumonectomy or lobectomy. Such studies are necessary to establish a rational basis for therapeutic intervention to arrest or prevent emphysema, since they will show (1) if the most severe lesions are associated with the greatest amount of elastase accumulation, (2) if the mildest emphysema shows the biggest repair-response, (3) if elastase is cleared from the lungs rapidly after cessation of smoking, and (4) if the concentration of elastin-derived peptides is highest in these patients with the most interstitial elastase.